R. Muirhead

Anal cancer: developing an intensity-modulated radiotherapy solution for ACT2 fractionation

Anal squamous cell carcinoma affects approximately 1100 patients per year in the UK, with the incidence increasing yearly [1]. The ACT2 trial, delivering radical chemoradiotherapy, determined the UK standard of care; reporting a complete response rates of 90% and a 3 year progression-free survival of 73% [2]. Due to the large parallel-opposed anterioreposterior/posterioreanterior (AP/PA) fields, there was significant associated acute toxicity; grade 3/4 gastrointestinal and haematological toxicity of 16 and 26%, respectively. Acute toxicity results in delays and interruptions; a concern, as there is evidence to suggest overall treatment time is associated with local control [3e5]. Finally, there is a lack of prospective data quantifying the recognised late side-effects on bowel, urinary and sexual function. Late bowel toxicity culminating in colostomy was seen in 2% of patients in the ACT2 trial [6]. Since the completion of ACT2 there have been significant developments in the staging and treatment of anal cancer. There is interest in improving latemorbidity bywithholding inguinal node irradiation in early disease. This has led to reports addressing the role of sentinel node biopsy and positron emission tomography/computed tomography in staging. Recent trials have individualized radiotherapy dose according to tumour size and nodal status. Finally, there has been widespread implementation of intensity-modulated radiotherapy (IMRT) to reduce acute toxicity and potentially dose-escalate selected patients. The Radiation Therapy Oncology Group (RTOG) 0529 phase II study, open from December 2006 to March 2008,

Modeling early haematologic adverse events in conformal and intensity-modulated pelvic radiotherapy in anal cancer.

Background and purpose To determine if there are differences between dose to pelvic bone marrow (PBM) using intensity modulated radiotherapy (IMRT) under UK guidance versus conformal radiotherapy (CRT) per ACT II protocol and if differences translate to rates of early haematological adverse events grade 3 or greater (HT3+). Methods and materials Two groups of 20+ patients, treated under IMRT and CRT regimes respectively, were identified. All patients underwent weekly blood cell count: haemoglobin (HgB), white cell count (WCC), absolute neutrophil count (ANC) and platelets (plats). Percent volume of PBM and sub structures receiving 5–25 Gy were tested for statistical significance. Regression models were used to test for correlation to blood counts. NTCP modeling was also performed. Results PMB dose metrics showed a significant increase in the IMRT group. Regression analysis showed iliac and lumbosacral PBM dose metrics to associate with reduced nadir ANC and WCC. NTCP at HT3+ was 0.13 using IMRT relative to 0.07 using CRT (p < 0.05). Conclusion Whilst this is a relatively small retrospective study and lacks information on the distribution of active PBM, IMRT treatment has been shown to significantly increase PMB irradiation. PBM dose metrics have been shown to be predictive of WCC and ANC suppression. NTCP modeling predicts much high risk of HT3+. Paradoxically, actual rates of HT3+ were comparable suggesting that differences in the distributions of dose metrics maybe a significant factor and/or that there are insufficiency in the NTCP modeling.

Rectal Radiotherapy--Intensity-modulated Radiotherapy Delivery, Delineation and Doses.

The use of intensity-modulated radiotherapy in rectal cancer is attractive in that it may reduce acute and late toxicities and potentially facilitate dose escalation. Intensity-modulated radiotherapy probably has a role in selected patients, but further investigation is required to identify the parameters for selection. Delineation of specific nodal groups allows maximal sparing of bladder and small bowel. In locally advanced tumours a simultaneous integrated boost allows dose escalation incorporating hypofractionation and a shorter overall treatment time. However, due to a sparsity of data on late toxicity in doses ≥ 60 Gy, doses at this level should be used with caution, ideally within prospective trials. Future studies investigating dose escalation must ascertain late toxicity as well as local control, as both can significantly affect quality of life and without both, the risk-benefit ratio cannot be calculated.

A tumor control probability model for anal squamous cell carcinoma

BACKGROUND AND PURPOSE A recent update of the RTOG 9811, reported differing relapse rates for early and late anal squamous cell carcinoma following chemoradiotherapy (CRT). There may be a role for dose-individualization, however the dose-response relationship for anal cancer is not currently known. Intensity-modulated radiotherapy (IMRT) has been widely adopted with multiple series published. The aim is to fit a tumor control probability (TCP) model to the published IMRT data. MATERIALS AND METHODS We performed a systematic review of PubMed and Embase databases to identify thirteen appropriate papers, including 625 patients. Predefined data fields were collected. A standard linear quadratic TCP model, which included repopulation, was fit by least squares minimization. RESULTS The fitted TCP curve demonstrated a dose-response relationship with α=0.196 Gy(-1). The curve suggests: in early stage tumours, a dose reduction from 50 Gy to 45 Gy reduces 2 year local control from 98% to 95%; in late stage tumours, a dose escalation from 50 Gy to 55 Gy improves the 2 year local control rate from approximately 50% to 80%. CONCLUSIONS The published data are broadly consistent with a linear quadratic dose-response model. Dose-individualization in anal cancer should be further investigated in the context of clinical trials.

Quantifying target-specific motion in anal cancer patients treated with intensity modulated radiotherapy (IMRT)

Background and purpose Intensity modulated radiotherapy requires all target areas to be treated by a single radiotherapy plan. In anal cancer, the pelvic nodes, inguinal nodes and primary tumour represent three different targets. We aim to calculate target-specific motion in anal cancer radiotherapy, when delivered using a single pelvic online auto-match. Materials and methods Twenty consecutive patients treated using IMRT at a single institution were studied. CBCTs were retrospectively re-matched around the inguinal nodes and primary tumour. Match values were recorded relative to origin, defined as pelvic CBCT auto-match. Systematic and random errors were quantified to determine target-specific motion and suggested margins calculated using van Herk formulae. Results The suggested margins to cover the independent motion of the inguinal and anal targets for LR, CC and AP set up around the inguinal nodes were 1.5 mm, 2.7 mm and 2.8 mm; and the primary tumour were, 4.6 mm, 8.9 mm and 5.2 mm respectively. Conclusions Target-specific set up will likely result in reduced treatment volumes and as such reduced toxicity. This is the first time a relationship has been described between pelvic bones, inguinal nodes and primary tumour. The PLATO study will prospectively assess the toxicity and outcomes of this target-specific margins strategy.

PO-0706: Individualised margin calculations for different target regions in anal cancer IMRT

Purpose/Objective: UK IMRT anal cancer treatment uses large fields to uninvolved nodal groups (40Gy) with simultaneous integrated boost to the primary tumour (50.4Gy T1/T2; 53.2Gy T3/T4) and involved nodes (50.4Gy). With a simple bony match online, iliac nodes are well covered and the margins required are well documented, however the margins for prophylactic inguinal nodes (pIN) and primary tumour are not well established as data from daily imaging are limited; these form the focus of this study. Materials and Methods: Anal cancer patients treated at a single institution under current UK IMRT guidelines were screened; 11 consecutive inguinal node negative patients were studied. Supine treatment comprised 28 fractions with daily imaging: CBCT fractions 1-5, 10, 15, 20 and 25; orthogonal kV imaging all other fractions. 99 CBCT’s were re-matched automatically to the planning CT. A bony match was performed using a clipbox encompassing the bony pelvis. Re-matches were performed within the same clipbox using the clinician defined tumour (GTVA) as a region of interest (ROI), then repeated with the pIN ROI. Accuracy of auto-matches were assessed visually to ensure clinical relevance. Bony match values were subtracted from the GTVA and pIN measurements to evaluate differences in the optimal treatment position for the tumour or the nodes relative to a simple bony match. Margins were calculated using van Herk’s recipe. Results: Differences (mm) between GTVA/ bony matches were larger than inguinal/ bony matches in all axes ( lat -3.1 to 4.2; -2 to 1.5, vert6.9 to 12.7; -3.6 to 2.9, long -13.3 to 17.2; -8.5 to 7.3 in GTV and pIN respectively). This was statistically significant in the long axis (p<0.05) shown in Fig.1. GTVA had consistently larger systematic and random errors than pIN, reflected in the margin calculations (mm): GTVA lat 2.8, long 9.8, vert 5.8; pIN lat 1.5, long 3.1, vert 3.1. Conclusions: With a simple bony match, the margin around pIN can be reduced to 1.5mm laterally and 3.1mm in all other directions potentially reducing toxicity to the groin, genitalia and bladder. The GTVA to PTV margin incorporates microscopic disease, the motion of the soft tissues of the anus which can be affected by tumour size, location, bowel filling and BMI; and the set up error. The margin reported in this study covers set up error and soft tissue motion of the anus. An individualised margin incorporating these factors can be calculated and applied during the treatment course with the aim of reducing toxicity in adjacent organs such as vagina, bladder and penile bulb. Further investigation is warranted to demonstrate reduced toxicities with these strategies.

Volumetric analysis of anal cancer relapses following radical chemoradiation.

576 Background: Definitive chemoradiotherapy is standard of care in anal squamous cell carcinoma. The ACT II trial set the standard achieving three year overall survival rates of 73%. However patients with locally advanced disease have a ~50% local relapse rate. Studies have failed to demonstrate an improvement in local relapse rate by altering the systemic therapy. Although 2/3 of relapses are local as opposed to regional or distant, there is limited knowledge on the 3D position of these relapses. We aim to retrospectively review the patterns of local failure in three dimensions, relative to the radiotherapy plan. Methods: Between February 2007 and April 2012, 77 patients were treated for squamous cell carcinoma of the anus with radical chemoradiotherapy. Early stage (T0/2) and locally advanced (T3/4) tumours constituted 53% and 44% respectively. 37% of patients had nodal disease. As per ACT II protocol we used a gross tumour volume (GTV) to PTV margin of 3cm and prescribed to a dose of 50.4Gy. In patien...